- answer the frequently asked questions on acute inflammation
- prepare for the theory and viva exams in pathology
- get an easy refence tool for mediators of inflammation which might prove useful in pharmacology (autacoids) and microbiology (immunity) as well
General Considerations
1. Define inflammation.
Inflammation is defined as the protective response of a living vascularised tissue to a sub-lethal injury.
2. What are the different types of inflammation?
Inflammation may be of two types:
a) Acute inflammation
b) Chronic inflammation
3. State the cardinal signs of inflammation.
The cardinal signs of inflammation are:
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
Functio laesa (loss of function)
4. Compare acute & chronic inflammation.
Acute inflammation
It is of short duration
Characterized by tissue destruction followed by repair
Principal cells of inflammation are neutrophils (microphage)
Exudate formation is a hallmark
Chronic inflammation
It is of longer duration
Characterised by the simultaneous progress of tissue destruction and repair
Principal cells of inflammation are macrophages, lymphocytes and plasma cells.
Exudate formation is not so promine
5. What are the mechanisms underlying the genesis of the cardinal signs of inflammation?
Rubor – Due to increased vasodilation
Dolor – Due to local injury & release of pain producing mediators of inflammation
Tumor – Due to transudation & exudation of fluids into tissue spaces
Calor – Due to increased rate of oxygen utilization in the local tissue (respiratory burst) and vasodilatation.
ACUTE INFLAMMATION
6. Enumerate different events of acute inflammation.
The different events of acute inflammation are:
A. Vascular changes:
a) Changes in vascular flow & caliber
b) Increased vascular permeability
B. Leukocyte cellular events
a. Margination & rolling
b. Adhesion & transmigration
c. Chemotaxis & activation
d. Phagocytosis & degranulation
e. Leukocyte induced tissue injury
7. Write a short note on Phagocytosis.
Definition: It is a process of endocytosis by which a cell engulfs a semisolid material with subsequent formation of a phagocytic vacuole.
Mechanism:
A) FORMATION OF ENDOSOME
Phagocytosis can be basically of two types - Constitutive phagocytosis and receptor mediated phagocytosis. Costitutive phagocytosis is a continuous process that is not induced by any agent. Receptors meditative phagocytosis is produced in most cases by specialized clathrin-coated pits on the cell membrane. The latter is triggered by various ligands binding to their receptors on the cell surface. After the pit is full of ligands, the pit pinches off, forming a coated vesicle. This coated vesicle is now called early endosome. Now the endosome gets separated from the membrane and moves into the cytosol. This is now called a late endosome.
B) TRANSPORT OF ENDOSOME
The transport of vesicles is guided by different groups of targeting and docking proteins. On the surface of the endosome (vesicle) there is a specific V-snare protein that latches with its corresponding T-snare protein on the target.
Various small GTP-binding proteins of the Rab family are associated with acceleration of the transport, where as proteins of Sec 1 family slow down the transport process.
C) FATE OF THE ENDOSOME
The late endosome fuses with lysosomes and lysosomal enzymes digest their contents.
Importance of Phagocytosis:
- It helps to kill bacteria. Bacteria can be killed by ROS-mediated, non-ROS-mediated (enzymatic) & NO-mediated mechanisms
- Phagocytosis of dead tissue by scavenger cells (macrophages) helps in clearing tissue debris
- Receptors mediated endocytosis helps in internalization of LDL, insulin, epidermal growth factor, nerve growth factor, diphtheria toxin and a no. of viruses.
8. What are the morphological patterns, which an acute inflammatory process can present?
Morphological patterns of acute inflammation:
- Catarrhal – Superficial inflammation of mucous surfaces with hyper secretion of mucus by goblet cells.
E.g. Common cold, Inflammation of bowel
- Serous – Formation of protein rich fluid exudates with minor cellular exudation
E.g. Peritonitis, Synovitis - Fibrinous – Here, exudates contains abundant fibrinogen which is precipitated as a thick fibrin coating
E.g. Fibrinous pericarditis, lobar pneumonia - Pseudo-membranous – Formation of a membrane made of fibrin, necrotic epithelium and inflammatory cells
E.g. Pseudo-membrane of diphtheria - Hemorrhagic – Associated with frank hemorrhage due to vascular damage by bacterial toxins
E.g. Secondary bacterial infection in viral pneumonia - Gangrenous – Inflammation associated with wide spread necrosis of the organ, probably resulting from superimposed thrombosis or vascular occlusion
E.g. Strangulated hernia - Purulent – Production of pus which is creamy yellow in color, high specific gravity, alkaline in reaction & semi fluid in consistency
E.g. Abscess, Empyema - Phlegmatous – Diffuse spread of exudates through loose and lax tissue spaces by virulent bacteria
E.g. Erysipelas of face - Allergic – Hyper sensitivity of the host immune system to an antigen which was previously introduced to the body
E.g. Bronchial asthma
NOTE: Q. Why is diphtheric inflammation called Pseudo-membranous?
In diphtheria the membrane that is formed does not contain any basement membrane. It is composed entirely of fibrin, necrotic tissue &cellular exudates; hence it is called pseudo-membranous.
9. What are the fates of acute inflammation?
The fates of acute inflammation are:
- Resolution
- Progression to suppuration
- Progression to chronic phase with fibrosis
10. What are the cells taking part in host immunity? State their roles in the process of inflammation?
Natural cytolytic cells
a) Natural killer cells – Large granular lymphocytes, having Fc receptors for antibodies and kill anti body coated cells and virus infected tumor cells
Phagocytic cells
a) Neutrophils – Granulocytes with multilobed nucleus; help in phagocytosis and kill bacteria
b) Eosinophils – Granulocytes with bilobed nucleus and coarse brick-red cytoplasmic granules; take part in parasite defense and allergic response
c) Macrophages – Present in tissue, spleen, lymph nodes; bears Fc and C3 receptors on cell surface; takes part in inflammatory response anti-viral and anti-tumor activities
Antigen-presenting cells (APCs)
a) Monocytes – agranulocytes with Horse-shoe shaped nucleus that modulates immune response by releasing various cytokines
b) Macrophages – as above
Antigen -responsive cells
a) CD4 T cells – Mature in thymus, characterized by large nucleus, small cytoplasm; contains CD2, CD3, TCR, CD4 molecules on cell surface; Secretes IL-1 and other lymphokines and stimulate T and B cell growth
b) CD8 T killer cells – Involved in recognition of antigen; bears CD2, CD3, TCR, CD8 molecules on surface; Kill viral, tumor, transplant cells and secretes IL-2, IFN-gamma
Antibody producing cells
a) B cells – Mature in bursal equivalent; presents surface antibodies and class II MHC molecules and involved in Antibody production
b) Plasma cells – Activated B cells with eccentric small nucleus with Russel bodies in the cytoplasm that serve as antibody factories
Other cells
a) Basophils / mast cells – Granulocytes with coarse blue cytoplasmic granules; bears Fc-receptor of Ig E on surface; involved in Histamine release and allergic reactions
11. Enumerate the chemical mediators of acute inflammation.
The different chemical mediators of acute inflammation are classified into:
- Cell-derived mediators
- Plasma-derived mediators
The cell derived mediators include:
a) Preformed mediators, like Histamine, Serotonin & Lysosomal enzymes
b) Newly synthesized mediators, like Prostaglandins, Leukotrienes, PAF, ROS, NO, Cytokines, etc
The plasma derived mediators include:
Active by-products of the clotting system, fibrinolytic system, kinin system & complement system
12. Mention the functions of the mediators of inflammation with examples.
The most likely mediators involved in the following inflammatory changes are:
Vasodilatation:
a) Prostaglandins
b) Nitric oxide
Increased vascular permeability:
a) Vasoactive amines
b) C3a and C 5a
c) Bradykinin
d) LT C4, D4, E4
e) PAF
Chemotaxis and leukocyte activation:
a) C5a
b) LT B4
c) Bacterial products
d) Chemokines
Fever:
a) IL1, IL6s
b) TNF-alpha
c) Prostaglandins
Pain:
a) Prostaglandins
b) Bradykinin
Tissue damage:
a) Lysosomal enzymes
b) ROS
c) NO
A BRIEF DISCUSSION ON SOME IMPORTANT MEDIATORS OF INFLAMMATION:
Histamine: -
Derived from the amino acid histidine by decarboxylation
Present in mast cells
Released in response to physical injury, typeI hypersensitivity, C3a and C5a of complement, leukocyte-derived histamine-releasing proteins, neuropeptides and some cytokines.
Causes arteriolar dilatation and increased vascular permeability, venular endothelial contraction and widening of inter-endothelial cell junction.
Inactivated by histaminase
Serotonin: -
Derived from amino acid tryptophan by 5-hydroxylation and decarboxylation. Also called 5-hydroxytryptamine or 5HT
Found within platelet- dense body granules
Release is stimulated by platelet aggregation
Function is similar to histamine
Arachidonic acid metabolites (Eicosanoids): -
These are derivatives of eicosa-tetra-eneoic acid (20carbon unsaturated fatty acid) viz. arachidonic acid
Arachidonic acid is liberated from membrane-phospholipid during cell injury by the enzyme phospholipase A2. This enzyme is inhibited by glucocorticoids
From arachidonic acid, by cycloxygenase enzyme (COX) the prostaglandins (PG) & thromboxanes (TX) are produced. This enzyme is inhibited by NSAIDs
From arachidonic acid by lipoxygenase enzyme (LOX) the leukotrienes (LT) are produced. This enzymes is inhibited by zileuton
Functions of eicosanoids are:
1. PG I2 (prostacyclin)
Vasodilatation
Inhibits platelet aggregation
2. TX-A2 (thromboxane)
Vasoconstriction
Promotes platelet aggregation
3. PG-D2, PG-E2, PG-F2 alpha
Vasodilation
Edema
4. LT-B4
Chemotaxis
5. LT-C4, LT-D4, LT-E4
Vasoconstriction
Bronchospasm
Increased vascular permeability
Platelet-activating factor (PAF): -
It is a phospholipid- derived mediator. Chemically it is acetyl glycerol ether phosphocholine
Obtained from membrane phospholipids of leukocytes and other cells by the action of phospholipase-A2
It causes vasoconstriction in high doses and vasodilation at low doses .in addition it also causes broncho-constriction, increased leukocyte adhesion, chemotaxis, leukocyte degranulation and oxidative burst. It can also stimulate synthesis of eicosanoids
Nitric oxide (NO): -
It is a short acting soluble gaseous free radical
It was initially called EDRF (endothelium-derived relaxation factor)
It is synthesized from L-Arginine with the help of NO-synthase
L-Arginine + O2 + NADPH = Citrulline + NO + NADP
The reaction is catalysed by NO-synthase
The enzyme NO synthase has 3 isoforms:
I. Neuronal isoform, present in neurons, and constitutive in nature. It is also called nc NOS
II. An inducible isoform present in cardiac myocytes, hepatocytes and respiratory epithelium, called i NOS
III. Another constitutive isoform present in endothelium, called ec NOS
Of these, the function of the constitutive iso-enzymes (I and III) depends on the cytosolic Ca++ level.
Functions of NO include:
a. Smooth muscle relaxation by stimulating soluble Guanylyl cyclase enzyme
b. Formation of peroxynitrite radical by combining with super oxide radical. This radical breaks into toxic NO2 and OH- radical
c. It can combine with iron in presence of thio-compounds (R-SH) to form di-thio di-nitroso complex with iron. This depletes iron and leads to inhibition of several bacterial enzymes.
Complement system: -
It is a group of about 20 plasma proteins that help in non specific immune response
It comprises of 2 distinct pathways – the classical pathway and the alternate pathway
Classical pathway comprises of sequential activation of number of plasma proteases following activation by immune-complex
Alternate pathway is activated by the cell wall lipo-polysaccharide of bacteria
Both the systems converge into a final common pathway leading to the formation of a Membrane Attack Complex (MAC) that induces pore formation in the membrane of cells and leads to osmotic lysis
Role of complement components in inflammation are:
a) C 3a and C5a increases vascular permeability (anaphylatoxin)
b) C5a is chemotactic to leukocytes
c) C3b is an important opsonin
d) C5b- C7 complex is a chemo tactic agent
e) C5b-9 is the MAC
Kinin system: -
This system comprises of 2 vasoactive peptides- bradykinin and lysyl-bradykinin (kalidin)
Bradykinin is a Nona peptide whereas lysyl-bradykinin is a deca peptide having an extra lysine residue at the amino-terminal
They are derived from the High and the Low molecular weight kininogens (HMWK and LMWK)
They are inactivated by kininase I and kininase II.Kininase II is identical with ACE
Function of kinins are:
a) Contraction of smooth muscle
b) Dilatation of arterioles
c) Production of pain
d) Chemotaxis
e) Increased vascular permeability
Clotting system: -
The coagulation system plays important roles in the mediation of inflammation
Activation of the Hageman factor (factor XII) is the key process leading to activation of the plasma proteases
Fibrino-peptides formed due to conversion of fibrinogen to fibrin leads to increased vascular permeability
The fibrino-peptides are also chemotactic to neutrophils
Fibrinolytic system: -
Converts fibrin into fibrinopeptides which lead to:
a) Increased vascular permeability
b) Chemotaxis
c) Generation of C 3a
d) Activation of kinin system
Lysosomal products: -
Lysosomal granules of neutrophils and monocytes contain different inflammatory mediators
The proteolytic substances include acid proteases and neutral proteases
Acid proteases have acidic pH optima and active only in phagolysosomes
Neutral proteases include elastase, collagenase and cathepsin, which degrade extra-cellular matrix (ECM). It can generate C3a and C5a, and stimulate kinin system
To counteract the uncontrolled effects of proteases, a number of anti-proteases are present in serum and ECM
References:
- Pathologic Basis of Disease – 7th ed, Robbins & Cotran
- General Pathology – Walter Israel
- Review of Medical physiology – 19th ed, W F Ganong
- Harper’s Biochemistry – 25th ed, Murray et al
- Immunology – Roitt
- Medical microbiology – 22nd Jawetz, Melnick & Adelberg
- Pharmacology – 6th ed, Rang, Dale, Ritter
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